p-Nitrobenzyl protection for cysteine and selenocysteine: A more stable alternative to the acetamidomethyl group

Muttenthaler, Markus, Ramos, Yesica Garcia, Feytens, Debby, Dantas de Araujo, Aline and Alewood, Paul F. (2010) p-Nitrobenzyl protection for cysteine and selenocysteine: A more stable alternative to the acetamidomethyl group. Biopolymers, 94 4: 423-432. doi:10.1002/bip.21502


Author Muttenthaler, Markus
Ramos, Yesica Garcia
Feytens, Debby
Dantas de Araujo, Aline
Alewood, Paul F.
Title p-Nitrobenzyl protection for cysteine and selenocysteine: A more stable alternative to the acetamidomethyl group
Formatted title
p-Nitrobenzyl protection for cysteine and selenocysteine: A more stable alternative to the acetamidomethyl group
Journal name Biopolymers   Check publisher's open access policy
ISSN 0006-3525
1097-0282
Publication date 2010-01-01
Year available 2010
Sub-type Article (original research)
DOI 10.1002/bip.21502
Open Access Status Not yet assessed
Volume 94
Issue 4
Start page 423
End page 432
Total pages 10
Place of publication Hoboken, NJ, United States
Publisher John Wiley & Sons
Language eng
Abstract This study evaluated the acidic lability of the acetamidomethyl (A cm), trimethylacetamidomethyl (Tacm), and the p-nitrobenzyl (pNB) as protecting groups for cysteine and selenocysteine (Sec) during the tert-butyloxycarbonyl (Boc)-chemistry solid-phase peptide synthesis of oxytocin (OT). Two novel Sec building blocks (N(alpha)-tert-butyloxycarbonyl-Se(acetamidomethyl)-L-selenocysteine (Boc-L-Sec(Acm)-OH) and N(alpha)-tert-butyloxycarbonyl-S(4-nitrobenzyl)-L-selenocysteine (Boc-L-Sec(pNB)-OH)) were developed for this study. Six partially protected thio- and seleno-OT analogues were synthesized, purified, and exposed to neat trifluoroacetic acid (TFA) at temperatures of 25, 40, 50, and 60 degrees C for 1 h, and HF treatment at 0 degrees C for 1 h. Significant losses were observed for the Acm and Tacm group in TFA at temperatures greater than 25 degrees C and during HF treatment at 0 degrees C, whereas the pNB group remained intact. Removal of the pNB was achieved via reduction to the p-aminobenzyl group either with zinc in acetic acid in solution or via tin chloride in hydrochloric acid on solid support, followed by oxidative cleavage with iodine yielding the corresponding disulfide or diselenide bond. No major side reactions were observed. This study confirms the occasionally described Acm instability and underpins the development of the pNB group as an alternative for cysteine and Sec protection. (C) 2010 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 94: 423-432, 2010.
Formatted abstract
This study evaluated the acidic lability of the acetamidomethyl (Acm), trimethylacetamidomethyl (Tacm), and the p-nitrobenzyl (pNB) as protecting groups for cysteine and selenocysteine (Sec) during the tert-butyloxycarbonyl (Boc)-chemistry solid-phase peptide synthesis of oxytocin (OT). Two novel Sec building blocks (Nα-tert-butyloxycarbonyl-Se(acetamidomethyl)-L-selenocysteine (Boc-L-Sec(Acm)-OH) and Nα-tert-butyloxycarbonyl-S(4-nitrobenzyl)-L-selenocysteine (Boc-L-Sec(pNB)-OH)) were developed for this study. Six partially protected thio- and seleno-OT analogues were synthesized, purified, and exposed to neat trifluoroacetic acid (TFA) at temperatures of 25, 40, 50, and 60°C for 1 h, and HF treatment at 0°C for 1 h. Significant losses were observed for the Acm and Tacm group in TFA at temperatures greater than 25°C and during HF treatment at 0°C, whereas the pNB group remained intact. Removal of the pNB was achieved via reduction to the p-aminobenzyl group either with zinc in acetic acid in solution or via tin chloride in hydrochloric acid on solid support, followed by oxidative cleavage with iodine yielding the corresponding disulfide or diselenide bond. No major side reactions were observed. This study confirms the occasionally described Acm instability and underpins the development of the pNB group as an alternative for cysteine and Sec protection.
© 2010 Wiley Periodicals, Inc.
Keyword Cys (Acm) lability
Oxytocin synthesis
p-nitrobenzyl protection
Solid-phase peptide synthesis
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Special Issue Dedicated to the 2009 Bruce Merrifield Award Winner Stephen B. H. Kent

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2011 Collection
Institute for Molecular Bioscience - Publications
 
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Created: Sun, 18 Jul 2010, 10:09:44 EST